DESCRIPTION (applicant's abstract): The focus of the proposed research program is on the kinetics and mechanisms of aggregate formation, and especially for processes that parallel beta-amyloid assembly and the closely related prion diseases. The principal investigator has previously developed non-conventional kinetic analyses for the formation of supramolecular assemblies of chromophores in which rate constants may themselves be time-dependent. These approaches hold promise for analyzing and interpreting kinetic profiles obtained for these pathological conditions. Insulin aggregates have been suggested as a model system for beta-amyloids. This peptide produces kinetic profiles very similar to those published by other workers for the authentic sequence, but permits exhaustive studies because of its availability. The proposed goals are: (i) to identify the rate-determining step of the aggregation process. Is the formation of a critical nucleus or seed required for aggregation to proceed and is this step rate-determining? (ii) to determine whether the process is autocatalytic for which the "'evolutionary autocatalytic"' model may be useful; (iii) to identify catalysts for the aggregation process, and determine the common features of these substances which make them effective catalysts; and (iv) perhaps most importantly, to identify inhibitors to assembly formation, and in particular, substances which can be tolerated by living organisms. The ultimate objective is the development of a sufficiently detailed understanding of the aggregation so that non-invasive strategies can be offered to inhibit the process.